Glaucoma is a chronic eye condition in which the nerve that connects the eye to the brain (optic nerve) is progressively damaged. Patients with early glaucoma do not have visual symptoms. Progression of the disease results in loss of peripheral vision, so patients may complain of “tunnel vision” (only being able to see the centre). Advanced glaucoma is associated with total blindness. Worldwide, it is the second leading cause of blindness, affecting 60 million people by 2010, and responsible for approximately 5.2 million cases of blindness (15% of the total burden of world blindness). The problem is even more significant in Asia, as Asians account for approximately half of the world's glaucoma cases. Finally, because it is a condition of aging, it will affect more people in Singapore and Asia as their population ages.
Recent years' development in the understanding of the genetics of glaucoma allows for the first time a molecular insight into the pathogenesis glaucoma. Ophthalmologists have long recognized the presence of a subgroup of glaucoma that follows a mendelian form of inheritance (recessive or dominant). With large enough families, linkage analysis is a very powerful technique that can quickly identify the culprit genes in these families. Moreover, even the more common forms of glaucoma which do not typically follow a clear mendelian pattern of inheritance, are known to cluster in families. This indicates the existence of “genetic predisposition” that may differ between various populations.
Two genes (MYOC and OPTN) have been shown to account for a small fraction of open-angle glaucoma cases. Moreover, the CYP1B1 gene has been found to be responsible for more than half of cases of congenital glaucoma in some populations studied. Many more regions around the genome have been identified as genetic risk factors for glaucoma but the actual genes involved have not been found. Future studies are expected to examine the roles of more glaucoma genes in populations.
Genome wide association studies (GWAS) look for associations between DNA sequence variants and phenotypes of interest. They do so by studying hundreds of thousands of individuals with different phenotypes, and determining their genotype at the positions of hundreds of thousands of single DNA mutations (single-nucleotide polymorphisms, SNPs). About 600 human GWASs have examined 150 diseases and traits, and found 800 SNP associations. They are useful in finding the molecular pathways of disease, but usually not useful in finding genes that predict risks of disease.
These studies normally compare the DNA of two groups of participants: people with the disease (cases) and similar people without (controls). Each person gives a sample of cells and DNA is extracted from these cells, and spread on gene chips, which can read millions of DNA sequences. These chips are read into computers, where they can be analyzed with bioinformatic techniques. Rather than reading the entire DNA sequence, these systems usually read SNPs that are markers for groups of DNA variations (haplotypes).
If genetic variations are more frequent in people with the disease, the variations are said to be associated with the disease. The associated genetic variations are then considered as pointers to the region of the human genome where the disease-causing problem is likely to reside.
Currently, new techniques of GWAS have not only successfully identified known SNPs that are associated with diseases such as Parkinson, AMD, diabetes and etc, they have also identified suspected SNPs that are associated with the disease.
Recently, researchers from Netherlands conducted a large-scale GWA study [1] on retinal optic disc parameters, including optic disc and vertical cup-disc ratio, both are highly heritable but genetically largely undetermined. The study analyzed datasets from several European population studies, found several genome-wide significant loci for optic disc area and vCDR respectively, and identified three susceptible loci that are associated with open-angle glaucoma.
Glaucoma cannot presently be cured, but treatment can prevent progression of the disease, so early detection is critical to prevent blindness. However, routine screening for glaucoma in the whole population is not cost effective and limited by poor sensitivity of current tests. However, screening may be useful for high risk individuals, such as first degree relatives of a glaucoma patient, older age (e.g., 65 years and older) and elderly Chinese women (who are at risk of angle closure glaucoma). So far no technique employing genetic information has been employed in screening patients or assessing risk factors, and indeed it may not be possible to extract sufficient information from genetic data alone to make a screening operation possible.
Furthermore, currently, there is no systematic way to detect and manage early glaucoma. Glaucoma patients are often unaware they have the condition, and visit ophthalmologist (eye doctors) only when severe visual loss is already present. Treatment at this stage is limited to surgery, is expensive, requires skilled personnel, and does not restore vision.
There are three current methods to detect glaucoma:
(1) Assessment of raised intraocular pressure (IOP),
(2) Assessment of abnormal visual field
(3) Assessment of damaged optic nerve
IOP measurement is neither specific nor sensitive enough to be an effective screening tool. Visual field testing requires special equipment only present in tertiary hospitals.
As for assessing damage to the optic nerve, FIGS. 1(a) and 1(b) show different structures of the optic disc (the location where the ganglion cell axons exit the eye to form the optic nerve) respectively in the case of a normal optic disc and a glaucomatous disc. The upper part of the FIGS. 1(a) and 1(b) is a cross-sectional view, while the lower part of the figures is a perspective view. Among other physiological features, the glaucomatous disc has a wider optic cup. Assessment of damaged optic nerves is more promising and superior to IOP or visual field testing, but requires a trained specialist (ophthalmologist), or specialized equipment such as the HRT (Heidelberg Retinal Tomography). Furthermore, optic disc assessment by an ophthalmologist is subjective and the availability of HRT is very limited because of the cost involved as well as a shortage of trained operators.
ARGALI [2] (an Automatic cup-to-disc Ratio measurement system for Glaucoma AnaLlysls), a cup-to-disc ratio is derived from a single, non-stereo fundus image, and used to automatically measure the optic nerve. The ARGALI system makes use of contour-based methods in the determination of the cup and disc, through analysis of pixel gradient intensity values throughout the retinal image. In some cases, where the gradient values are gradual, difficulties in the correct cup identification can occur.
In [3] obtains a cup contour based on color space analysis of a non-stereo fundus image, based on pixel color. This technique has the weakness that the color information may not be accurate.
In [4], analysis of blood vessel architecture was used to determine the location of the cup within the optic disc. Using this method, bends in the retinal vasculature over the cup/disc boundary, also known as kinks, were used to determine the physical location of the optic cup. Although this method is non-reliant on color or pallor, some of the challenges include correct identification of kinks, as well as the absence of kinks in some retinal images.
In [5], discriminatory color-based analysis was used to determine the location of the cup and disc from retinal images. Histogram color analysis was performed on the image to determine the threshold cutoff between the cup and the disc. To determine the disc, statistical analysis of the pixel intensities was performed on the retinal image different features. However, no results were presented on the accuracy of results compared to clinical ground truth.
Some other work has also been presented [6, 7] making use of information from stereo photographs for the determination of the optic cup and disc. While some of the results presented are promising, the key challenge lies in the use of stereoscopic photography as compared to monocular (“non-stereo”) photography. Stereoscopic photography demands specific hardware and requires specialized training, both of which may be unsuitable for the needs for mass screening.